Abstract
T lymphocytes of the strain BALB/cHeA exhibit a low proliferative response to IL-2 and a high response to the anti-CD3 monoclonal antibodies, while the strain STS/A lymphocyte response to these stimuli is the opposite. We analyzed the genetic basis of this strain difference, using a novel genetic tool: the recombinant congenic strains (RCS). Twenty BALB/c-c-STS/Dem (CcS/Dem) RCS were used, each containing a different random set of approximately 12.5% of the genes from STS and the remainder from BALB/c. Consequently, the genes participating in the multigenic control of a phenotypic difference between BALB/c and STS become separated into different CcS strains where they can be studied individually. The strain distribution patterns of the proliferative responses to IL-2 and anti-CD3 in the CcS strains are different, showing that different genes are involved. The large differences between individual CcS strains in response to IL-2 or anti-CD3 indicate that both reactions are controlled by a limited number of genes with a relatively large effect. The high proliferative response to IL-2 is a dominant characteristic. It is not caused by a larger major cell subset size, nor by a higher level of IL-2R expression. The response to anti-CD3 is known to be controlled by polymorphism in Fcγ receptor 2 (Fcgr2) and the CcS strains carrying the low responder Fcgr2 allele indeed responded weakly. However, as these strains do respond to immobilized anti-CD3, while the STS strain does not, and as some CcS strains with the BALB/c allele of Fcgr2 are also low responders, additional gene(s) of the STS strain strongly depress the anti-CD3 response. In a backcross between the high responder and the low responder strains CcS-9 and CcS-11, one of these unknown genes was mapped to the chromosome 10 near D10Mit14. The CcS mouse strains which carry the STS alleles of genes controlling the proliferative response to IL-2 and anti-CD3 allow the future mapping, cloning, and functional analysis of these genes and the study of their biological effects in vivo.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
BMDP Statistical Software Manual, Vol. 1 and 2. University of California Press, Berkeley, CA, USA
De Waal Malefyt, R., Figdor, C. G., Huijbens, R., Mohan-Peterson, S., Bennett, B., Culpepper, J., Dang, W., Zurawski, G., and de Vries, J. E. Effect of IL-13 on phenotype, cytokine production, and cytotoxic function of human monocytes. J Immunol 151: 6370–6381, 1993
Demant, P. Genetic resolution of susceptibility to cancer — new perspectives. Sem Cancer Biol 3: 159–166, 1992
Demant, P. and Hart, A. A. M. Recombinant congenic strains: a new tool for analyzing genetic traits determined by more than one gene. Immunogenetics 24: 416–422, 1986
Demant, P., Oomen, L. C. J. M., and Oudshoorn-Snoek, M. Genetics of tumor susceptibility in the mouse: major histocompatibility complex and non-MHC genes. Adv Cancer Res 53: 117–179, 1989
Downward, J., Graves, J., and Cantrell, D. The regulation and function of p21ras in T cells. Immunol Today 13: 89–92, 1992
Fijneman, R. J. A., Ophoff, R. A., Hart, A. A. M., and Demant, P. Kras-2 alleles, mutations, and lung tumor susceptibility in the mouse — an evaluation. Oncogene 9: 1417–1421, 1994
Gajewski, T. F., Schell, S. G., and Fitch, F. W. Evidence implicating utilization of different T cell receptor-associated signaling pathways by TH1 and TH2 clones. J Immunol 144: 4110–4120, 1990
Gillis, M., Ferm, M. M., Ou, W., and Smith, K. A. T-cell growth factor: parameters of production and a quantitative microassay for activity. J Immunol 120: 2027–2032, 1978
Groot, P. C., Moen, C. J. A., Dietrich, W., Stoye, J. P., Lander, E. S., and Demant, P. The recombinant congenic strains for analysis of multigenic traits: genetic composition. FASEB J 6: 2826–2835, 1992
Groot, P. C., Moen, C. J. A., Hart, A. A. M., Snoek, M., and Demant, P. Recombinant congenic strains: genetic composition. In M. F. Lyon and A. G. Searle (eds.): Genetic Variants and Strains of the Laboratory Mouse, Third Edition, Oxford University Press, Oxford, in press
Hibbs, M. L., Hogart, P. M., and McKenzie, I. F. C. The mouse Ly-17 locus identifies a polymorphism of the Fc receptor. Immunogenetics 22: 335–348, 1985
Holáň, V., Lipoldová, M., Takáč, M., Černá, J., Vaňcatová, A., Cechová, D., Veselsky, L., and Hašek, M. Establishment and characterization of a permanent T-cell line producing an antigen non-specific factor. Immunology 56: 275–283, 1985
Huang, L. and Crispe, N. Superantigen-driven peripheral deletion of T cells. J Immunol 151: 1844–1851, 1993
Jenkins, M. K. and Johnson, J. G. Molecules involved in T-cell costimulation. Curr Opin Immunol 5: 361–367, 1993
Julius, M. H., Simpson, E., and Herzenberg, L. A. A rapid method for the isolation of functional thymus-derived murine lymphocytes. Eur J Immunol 3: 645–649, 1973
Klein, G. O. and Taylor, B. A. Possible localization of genes unlinked to the H-2 complex that control NK activity of BXD recombinant inbred strains. In E. Skamene (ed.): Genetic Control of Host Resistance to Infection and Malignancy, pp. 757–762, Alan R. Liss, Inc., New York, 1985
Ledbetter, J. A. and Herzenberg, L. A. Xenogeneic monoclonal antibodies to mouse lymphoid differentiation antigens. Immunol Rev 47: 63–90, 1979
Linsley, P. S., Brady, W., Grosmaire, L., Aruffo, A., Damle, N. K., and Ledbetter, J. A. Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation. J Exp Med 173: 721–730, 1991
Linsley, P. S., Brady, W., Urnes, M., Grosmaire, L. S., Damle, N. K., and Ledbetter, J. A. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med 174: 561–569, 1991
Lipoldová, M., Zajícová, A., Štědra, J., and Holán, V. Exogenous interleukin-2 abrogate's differences in the proliferative responses to T cell mitogens among inbred strains of mice. Cell Immunol 142: 177–185, 1992
Lowenthal, J. W., Corthésy, P., Tougne, C., Lees, R., MacDonald, H. R., and Nabholz, M. High and low affinity IL-2 receptors: analysis by IL-2 dissociation rate and reactivity with monoclonal anti-receptor antibody PC61. J Immunol 135: 3988–3994, 1985
Malek, T. R., Shevach, E. M., and Danis, K. M. Activation of T lymphocytes through the Ly-6 pathway is defective in A strain mice. J Immunol 143: 439–445, 1989
Minami, Y., Kono, T., Miyazaki, T., and Taniguchi, T. The IL-2 receptor complex: its structure functions, and target genes. Annu Rev Immunol 11: 245–267, 1993
Miyajima, A., Kitamura, T., Harada, N., Yokota, T., and Arai, K.-I. Cytokine receptors and signal transduction. Annu Rev Immunol 10: 295–331, 1992
Moen, C. J. A., van der Valk, M. A., Snoek, M., van Zutphen, L. F. M., von Deimling, O., Hart, A. A. M., and Demant, P. The recombinant congenic strains: a novel genetic tool applied to the study of colon tumor development in the mouse. Mammalian Genome 1: 217–227, 1991
Moen, C. J. A., Snoek, M., Hart, A. A. M., and Demant, P. Scc-1, a novel colon cancer susceptibility gene in the mouse: linkage to CD44 (Ly-24, Pgp-1) on chromosome 2. Oncogene 7: 563–566, 1992
Mori, N., Okumoto, M., van der Valk, M. A., Imai, S., Haga, S., Esaki, K., Hart, A. A. M., and Demant, P. Genetic dissection of susceptibility to radiation-induced apoptosis of thymocytes and detection of Rapop 1: a novel susceptibility gene. Genomics, in press
Peterson, V. M., Madonna, G. S., and Vogel, S. N. Differential myelopoietic responsiveness of BALB/c (Itys) and CD2 (Ityr) mice to lipopolysaccharide administration and Salmonella typhimurium infection. Infect Immun 60: 1375–1384, 1992
Pierres, A., Naquet, P., van Agthoven, A., Bekkhoucha, F., Denizot, F., Mishal, Z., Schmitt-Verhults, A. M., and Pierres, M. A rat antimouse T4 monoclonal antibody (H129.19) inhibits the proliferation of la-reactive T-cell clones and delineates two phenotypically distinct (T4 + Lyt-2,3- and T4-Lyt-2,3+) subsets among anti-la cytolytic T cell clones. J Immunol 132: 2776–2782, 1984
Roberts, M., Mock, B. A., and Blackwell, J. M. Mapping of genes controlling Leishmania major infection in CXS recombinant inbred mice. Eur J Immunogenet 20: 349–362, 1993
Schwartz, R. H. Costimulation of T lymphocytes: The role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy. Cell 71: 1065–1068, 1992
Tamura, T., Mizuguchi, J., and Nariuchi, H. Regulatory role of CD4/ L3T4 molecules in IL-2 production by affecting intracellular Ca2+ concentration of T cell clone stimulated with soluble anti-CD3. J Immunol 145: 78–84, 1990
Tax, W. J. M., Willems, H. W., Reekers, P. P. M., Capel, P. J. A., and Koene, R. A. P. Polymorphism in mitogenic effect of IgG1 monoclonal antibodies against T3 antigen on human T cells. Nature 304: 445–447, 1983
Todd, J. A., Aitman, T. J., Cornall, R. J., Ghosh, S., Hall, J. R. S., Hearne, C. M., Knight, A. M., Love, J. M., McAleer, M. A., Prins, J.-B., Rodrigues, N., Lathrop, M., Pressey, A., DeLarato, N. H., Peterson, L. B., and Wickers, L. S. Genetic analysis of autoimmune type 1 diabetes mellitus in mice. Nature 351: 542–547, 1991
Tomonari, K. A rat antibody against a structure functionally related to the mouse T-cell receptor/T3 complex. Immunogenetics 28: 455–458, 1988
Ullman, K. S., Northrop, J. P., Verweij, C. L., and Crabtree, G. R. Transmission of signals from the T lymphocyte antigen receptor to the genes responsible for cell proliferation and immune function: the missing link. Annu Rev Immunol 8: 421–452, 1990
Wang, R., Murphy, K. M., Loh, D. Y., Weaver, C., and Russell, J. H. Differential activation of antigen-stimulated suicide and cytokine production pathways in CD4+ T cells is regulated by the antigen-presenting cell. J Immunol 150: 3832–3842, 1993
Wegener, A.-M. K., Letourner, F., Hoeveler, A., Brocker, T., Luton, F., and Malisen, B. The T cell receptor/complex is composed of at least two autonomous transduction modules. Cell 68: 83–95, 1992
Wicker, L. S., Appel, M. C., Dotta, F., Pressey, A., Miller, B. J., DeLarato, N. H., Fischer, P. A., Boltz Jr., R. C., and Peterson, L. B. Autoimmune syndromes in major histocompatibility complex (MHC) congenic strains of nonobese diabetic (NOD) mice. The NOD MHC is dominant for insulitis and cyclophosphamide-induced diabetes. J Exp Med 176: 67–77, 1992
Wysocki, L. J. and Sato, V. L. Panning for lymphocytes: a method for cell selection. Proc Natl Acad Sci USA 75: 2844–2848, 1978
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Lipoldová, M., Kosařová, M., Zajícová, A. et al. Separation of multiple genes controlling the T-cell proliferative response to IL-2 and anti-CD3 using recombinant congenic strains. Immunogenetics 41, 301–311 (1995). https://doi.org/10.1007/BF00172155
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF00172155